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Maternal Hyperlipidemia Mediates Elevated Blood Pressure in Offspring Associated with Reprogramming Leptin Levels

41 Pages Posted: 2 Jul 2019

See all articles by Xian-Hua Lin

Xian-Hua Lin

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Yi-Meng Xiong

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Shen Tian

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Christian Klausen

University of British Columbia (UBC) - Department of Obstetrics and Gynecology

Meng-Xi Guo

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Qian Gao

Zhejiang University - Department of Pathology and Pathophysiology

Miao-E Liu

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Hui Wang

Maternity and Child Health Hospital of Songjiang District

Ling Gao

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Dan-Dan Wu

Shanghai Jiao Tong University (SJTU) - International Peace Maternity and Child Health Hospital; Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Cheng-Liang Zhou

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Jing Yang

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Ye Meng

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Ye Liu

Shanghai Jiao Tong University (SJTU) - International Peace Maternity and Child Health Hospital; Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Gu-Feng Xu

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Yong-Chao Lu

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Ya-Jing Tan

Shanghai Jiao Tong University (SJTU) - International Peace Maternity and Child Health Hospital; Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Kamran Ullah

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Yi-Min Zhu

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Williams D. Fraser

Université de Sherbrooke - Centre Hospitalier Universitaire de Sherbrooke

Jian-Zhong Sheng

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education); Zhejiang University - Department of Pathology and Pathophysiology

Peter C. K. Leunge

University of British Columbia (UBC) - Department of Obstetrics and Gynaecology

Louis Muglia

University of Cincinnati - Division of Human Genetics

Yan-Ting Wu

Shanghai Jiao Tong University (SJTU) - International Peace Maternity and Child Health Hospital; Shanghai Jiao Tong University (SJTU) - Institute of Embryo-Fetal Original Adult Disease

He-Feng Huang

Shanghai Jiao Tong University (SJTU) - International Peace Maternity and Child Health Hospital; Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education); Shanghai Jiao Tong University (SJTU) - Shanghai Key Laboratory of Embryo Original Diseases; Shanghai Jiao Tong University (SJTU) - Institute of Embryo-Fetal Original Adult Disease; Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

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Abstract

Background: Abnormal gestation energy metabolism is linked to major adult diseases in offspring. The aim of this study is to investigate whether leptin, as a mediator of energy metabolism, is involved in reprogramming the blood pressure control in offspring of mother with gestational hyperlipidemia.

Methods: Third trimester serum lipid profiles were analyzed in 2687 Han Chinese women. Leptin levels were examined in newborns and preschool aged offspring. 4863 Han Chinese people, including 1784 children and 3079 adults, were recruited for the evaluation of association between birth weight and blood pressure. A high-fat-diet (HFD) pregnant rat model was also established.

Results: Children born to gestational hypertriglyceridemia presented significantly higher rates of neonatal macrosomia and elevated serum leptin levels after birth. Leptin levels in both newborns and preschool age children were positively correlated with maternal triglyceride levels. Adults who were macrosomic at birth had increased blood pressures and higher incidence rates of hypertension though their BMIs had returned to normal. In rat, higher maternal lipid levels linked to sustained elevated leptin levels in offspring and were associated with increased blood pressure even with normal body weight. High maternal lipid profile induced leptin promoter hypomethylation and up-regulation of TET1, both in rat adipose tissues and lymphocytes as well as in human lymphocytes. Treatment of mesenchymal stem cells with free fatty acid during adipogenic differentiation also resulted in increased leptin and TET1 expression as well as leptin promoter hypomethylation.

Interpretation: Maternal hyperlipidemia during pregnancy mediates elevated blood pressure in offspring via reprogramming leptin levels.

Trial Registration: The Chinese Clinical Trial Registry (ChicCTR-OCH-14004536).

Funding Statement: This study was funded by The National Key Research and Development Program of China (2017YFC1001303 to H.F.H), National Natural Science Foundation of China (81801541 to D.D.W and 81601238 to L.G), International Cooperation Project of China and Canada NSFC (81661128010 to H.F.H), and the Chinese National Key Research and Development Award (2018YFC1004600 to L.J.M).

Declaration of Interests: The authors state that they have no conflict of interest to disclose.

Ethics Approval Statement: The study was a hospital-based cross-section study approved by the Research and Ethics Committee of the University Hospital of China, and informed consent from each participant was obtained.

Animal care and management were in accordance with the institutional guidelines for laboratory animals established by the Animal Care and Use Committee (ACUC), and were approved by the ACUC, School of Medicine, Zhejiang University, Hangzhou, China.

Keywords: Maternal hyperlipidemia; blood pressure; offspring; reprogramming; leptin

Suggested Citation

Lin, Xian-Hua and Xiong, Yi-Meng and Tian, Shen and Klausen, Christian and Guo, Meng-Xi and Gao, Qian and Liu, Miao-E and Wang, Hui and Gao, Ling and Wu, Dan-Dan and Zhou, Cheng-Liang and Yang, Jing and Meng, Ye and Liu, Ye and Xu, Gu-Feng and Lu, Yong-Chao and Tan, Ya-Jing and Ullah, Kamran and Zhu, Yi-Min and Fraser, Williams D. and Sheng, Jian-Zhong and Leunge, Peter C. K. and Muglia, Louis and Wu, Yan-Ting and Huang, He-Feng and Huang, He-Feng, Maternal Hyperlipidemia Mediates Elevated Blood Pressure in Offspring Associated with Reprogramming Leptin Levels (June 28, 2019). Available at SSRN: https://ssrn.com/abstract=3411710 or http://dx.doi.org/10.2139/ssrn.3411710

Xian-Hua Lin

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Yi-Meng Xiong

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Shen Tian

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Christian Klausen

University of British Columbia (UBC) - Department of Obstetrics and Gynecology

4500 Oak Street, #B242,
Vancouver, BC V6H 3N1.
Canada

Meng-Xi Guo

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Qian Gao

Zhejiang University - Department of Pathology and Pathophysiology

Hangzhou, 310058
China

Miao-E Liu

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Hui Wang

Maternity and Child Health Hospital of Songjiang District

Shanghai
China

Ling Gao

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Dan-Dan Wu

Shanghai Jiao Tong University (SJTU) - International Peace Maternity and Child Health Hospital

1961 Huashan Rd
Shanghai Shi, 200030
China

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Hangzhou, 310058
China

Cheng-Liang Zhou

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Jing Yang

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Ye Meng

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Ye Liu

Shanghai Jiao Tong University (SJTU) - International Peace Maternity and Child Health Hospital

1961 Huashan Rd
Shanghai Shi, 200030
China

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Gu-Feng Xu

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Yong-Chao Lu

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Ya-Jing Tan

Shanghai Jiao Tong University (SJTU) - International Peace Maternity and Child Health Hospital

1961 Huashan Rd
Shanghai Shi, 200030
China

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Hangzhou, 310058
China

Kamran Ullah

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Yi-Min Zhu

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Hangzhou, 310058
China

Williams D. Fraser

Université de Sherbrooke - Centre Hospitalier Universitaire de Sherbrooke

Quebec
Canada

Jian-Zhong Sheng

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Hangzhou, 310058
China

Zhejiang University - Department of Pathology and Pathophysiology

Hangzhou, 310058
China

Peter C. K. Leunge

University of British Columbia (UBC) - Department of Obstetrics and Gynaecology

950 W 28th Ave
Vancouver, British Columbia BC V5Z 4H4
Canada

Louis Muglia

University of Cincinnati - Division of Human Genetics

Cincinnati, OH 45221-0389
United States

Yan-Ting Wu

Shanghai Jiao Tong University (SJTU) - International Peace Maternity and Child Health Hospital ( email )

1961 Huashan Rd
Shanghai Shi, 200030
China

Shanghai Jiao Tong University (SJTU) - Institute of Embryo-Fetal Original Adult Disease ( email )

China

He-Feng Huang (Contact Author)

Shanghai Jiao Tong University (SJTU) - International Peace Maternity and Child Health Hospital ( email )

1961 Huashan Rd
Shanghai Shi, 200030
China

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China

Shanghai Jiao Tong University (SJTU) - Shanghai Key Laboratory of Embryo Original Diseases ( email )

Shanghai
China

Shanghai Jiao Tong University (SJTU) - Institute of Embryo-Fetal Original Adult Disease ( email )

China

Zhejiang University - Key Laboratory of Reproductive Genetics (Ministry of Education)

Zhejiang, 310058
China